P982: EFFICACY AND SAFETY OF 40 MG VS 60 MG OF ONCE WEEKLY SELINEXOR IN COMBINATION WITH POMALIDOMIDE AND DEXAMETHASONE IN RELAPSED AND/OR REFRACTORY MULTIPLE MYELOMA (RRMM)
Authors: Darrell White, Muhamed Baljevic, Gary Schiller, Suzanne Lentzsch, Evgeni Chubar, Noa Lavi, Dane Van Domelen, Ohad Bentur, Sumit Madan
Journal: HemaSphere (2023)

Topic: 14. Myeloma and other monoclonal gammopathies - Clinical Background: Selinexor is an oral exportin 1 inhibitor approved with low-dose dexamethasone + bortezomib for patients (pts) with previously treated multiple myeloma (MM). Prior studies have reported an overall response rate (ORR) of 28% and a median progression free survival (mPFS) of 3.7 months to pomalidomide + low dose dexamethasone (Pd) in pts with MM refractory to both bortezomib and lenalidomide. STOMP is an ongoing Phase 1b/2 study evaluating selinexor in various triplet/quadruplet combinations in pts with newly diagnosed and relapsed/refractory MM (NCT02343042). In the selinexor + Pd (SPd) arm of the STOMP study, selinexor was evaluated at doses of 60-80 mg twice weekly (BIW; weeks 1-3 only) or 40-100 mg once weekly (QW) in combination with pomalidomide 2-4 mg once daily (QD, days 1-21) and dexamethasone 40 mg weekly) in 28-day treatment cycles. Aims: To identify the optimal dose of SPd, two expansion cohorts, with selinexor 60 mg QW (SPd-60) or 40 mg QW (SPd-40), both with pomalidomide 4 mg QD, were enrolled in STOMP and XPORT-MM-028, a parallel study with similar objectives and eligibility criteria (NCT04414475). Methods: We analyzed data of pts with RRMM treated with SPd in the STOMP and XPORT-MM-028 studies. Efficacy and safety of the combination were analyzed and compared by dose. Results: As of Sept 6, 2022, 28 pts with a median of 2.0 prior treatment lines (mLOT) and 20 pts with 2.5 mLOT were enrolled in the SPd-40 cohort and SPd-60 cohort, respectively. Among pts treated with SPd-40 and SPd-60, 93% and 75% had MM refractory to a proteasome inhibitor (PI), 75% and 85% had MM refractory to an immunomodulatory drug (IMiD), and 43% and 20% had triple-class refractory MM refractory to an anti-CD38 monoclonal antibody (αCD38 mAb), a PI and an IMiD, respectively. Prior exposure to αCD38 mAbs was reported in 57% and 30% of pts in the SPd-40 and SPd-60 cohorts, respectively. Median duration of exposure in the SPd-40 vs SPd-60 cohorts was 28 vs 22 weeks. Numerically higher ORR and rate of pts with ≥very good partial response (VGPR) were observed for SPd-60 vs SPd-40 (ORR: 65% vs 50%; ≥VGPR: 30% vs 25%), but the PFS was numerically longer for SPd-40 vs SPd-60 (mPFS in months: not reached [95% CI, 6.5-NE] after median follow-up of 1 year vs 9.5 months [95% CI, 7.6-NE]; 9-month PFS probability: 0.59 [95% CI, 0.41-0.85] vs 0.52 [95% CI, 0.29-0.94]). Across both doses among pts previously treated with αCD38 mAbs (n=22), mPFS was 8.9 months (95% CI, 6.5-NE). For the 27 responders across both doses, median time to response was 1.0 month (95% CI, 1-2) and median duration of response was 21.8 months (95% CI, 8.6-NE). Common hematologic treatment-emergent adverse events (TEAEs) included (all grades: SPd-40 vs SPd-60) neutropenia (68% vs 75% with one case of grade 3 febrile neutropenia in each cohort), anemia (39% vs 65%) and thrombocytopenia (43% vs 45%). No high-grade hemorrhages were observed. Non-hematologic TEAEs were generally transient and reversible, including fatigue (43% vs 75%), nausea (32% vs 70%) and diarrhea (25% vs 35%). Summary/Conclusion: The all-oral combination of selinexor + Pd in pts with RRMM was effective and tolerable in these cohorts. Most TEAEs, including nausea, occurred at lower frequency in the 40 mg cohort. Although a higher 60 mg QW selinexor dose may be associated with a higher ORR, mPFS correlated with longer duration on treatment is numerically longer for pts treated with the 40 mg dose, suggesting that clinical benefit is optimized at the lower 40 mg dose. SPd is being further evaluated in the EMN29 Phase 3 study (NCT05028348). Keywords: Multiple myeloma, Clinical trial, relapsed/refractory, Therapy